Hepatitis C infection caused by HCV is among the most common liver diseases; widespread throughout the world. On the basis of annual World Health Organization (WHO) reports, more than 130-150 million people are infected and more than 350-500 K individuals die from HCV-related liver pathologies [WHO fact sheet N0 164. Hepatitis C; World Health Organization: Geneva, updated July 2013]. In accordance with the Centers for Disease Control and Prevention statistical estimation, approximately 3.2 million people chronically infected in the USA [Hepatitis C. Information for Health Professionals; Centers for E Control: Atlanta]. Acute disease states are frequently observe long-term and asymptomatic periods. Approximately 75-85% of newly infected persons become chronically infected. Among these patients, 60-70% will suffer chronic liver disease. In 5-20% of cases, cirrhosis or liver cancer is diagnosed, resulting in 1-5% lethal outcomes. It is not surprising that HCV is the leading indication for liver transplantation [Germani, G. et al. HCV in liver transplantation. Semin. Immunopathol. 2013, 35 (1), 101-110].
Based on the foregoing, there exists a significant need to identify compounds that are pan-genomic inhibitors of the NS5A protein encoded by HCV.
A number of NS5A inhibitors are currently undergoing clinical trials or already used for the treatment of hepatitis C including Daclatasvir (BMS-790052) [Belema, M. et al. J. Med. Chem. 57, 1643-1672, 2014, WO 2008/021927, WO 2008/021928, WO-2008/021936], Ledipasvir (GS-5885) [Link, J. et al. J. Med. Chem. 57, 2033-2046, 2014, WO 2010/132601], Ombitasvir (ABT-267) [DeGoey, et al. J. Med. Chem. 57, 2047-2057, 2014, WO 2010/144646], Elbasvir (MK-8742) [Coburn, C. A. et al. Chem Med Chem. 8, 1930-1940, 2013, WO 2012/040923, WO 2012/041014], Hepavivir (AV-4025) [Ivathtchenko, A. V. et al. J. Med. Chem. 57, 7716-30, 2014, WO 2012/074437] (Table 1).

TABLE 1The activity and bioavailability of known HCV NS5A inhibitors.EC50, pMHCV Genotype NS5ABioavailabilityNS5A inhibitorsGT1aGT1bGT2aGT3aGT4aGT5ain rat, F, %Daclatasvir (BMS-790052), BMSa50971103123311.0bLedipasvir (GS-5885), Giliadc 31a 5a20,800a10,100a  7a32.5AV-4025, AllaChemd 59b 3.4d 51b 2,5691217265.0Ombitasvir (ABT-267), Abbota,e  14.15  12.4  19.3  1.74.36.2Elbasvir (MK-8742), Mercka,f 43 3 20 39.0aBelema, M. et al. (2014) J. Med. Chem. 57, 1643-1672.b[hyperlink removed]cLink, J. et al. (2014) J. Med. Chem. 57, 2033-2046.dIvachtchenko, A. V. et al. (2014) J. Med. Chem. 57, 7716-7730.eDeGoey, et al. (2014). J. Med. Chem. 57, 2047-2057.fCoburn, C. A. et al. (2013). ChemMedChem. 8, 1930-1940.
However, known inhibitors possess some drawbacks. Thus, the pan-genomic HCV NS5A inhibitors Daclatasvir, Ombitasvir, and Elbasvir have limited bioavailability (Table 1), and Ledipasvir and AV-4025 have insufficient activities against GT3a and GT5a of HCV NS5A. In this context, searching for new pan-genomic HCV NS5A inhibitors with improved characteristics is an important task.